Project Description The threat of relapse to opioid use is severe and unrelenting: 40-60% of individuals who misuse or become addicted to opioids relapse weeks or months after opioid withdrawal. Profound sleep disturbances during abstinence have long been suspected of perpetuating vulnerability to relapse. Our research in the animal model has shown that long-term sleep deficiency results in a persistent state of physiological dysregulation that is expected to modify the biology of abstinence and increase relapse potential. The objective of this proposal is to discover how persistent sleep restriction during withdrawal from opioid use increases vulnerability to relapse in the animal model. This project will focus on the period of abstinence because it offers a crucial opportunity for intervention. We will test the hypothesis that persistent sleep restriction during abstinence from opioid use is sufficient to increase opioid drug seeking, rather than merely being a comorbidity. Under Aim 1, we will evaluate the effects of persistent sleep deficiency on opioid seeking. Male and female rats withdrawn from self- administration of oxycodone will either be sleep restricted or allowed to sleep ad libitum for several weeks under carefully-controlled, validated procedures. This will allow changes in phenotype resulting from sleep restriction to manifest and interact with the biology of abstinence. The rats will then be tested for changes in opioid seeking, which is a clear functional outcome with translational value. Studies under Aim 2 will focus on the combined interaction between persistent sleep deficiency and abstinence from opioid use on hypothalamic-pituitary- adrenal (HPA) axis activity. The HPA axis?which is at the core of the physiological response to stress and vulnerability phenotypes?affects upstream and downstream pathways implicated in opioid drug use. Rodent models of opioid craving have demonstrated that blockade of glucocorticoid signaling, or inhibition of glucocorticoid synthesis, increases the ability of both re-exposure to a drug environment and stress to trigger opioid seeking. Our preliminary data and feasibility studies show that persistent sleep deficiency alone results in a dysregulated HPA axis which therefore may underlie vulnerability. We will interrogate the HPA axis to isolate the mechanism that is maintained in a dysregulated state by persistent sleep restriction during abstinence and determine if the mechanism is responding to pharmacological challenges differently in male and female subjects. We will chronically intervene in HPA axis activity during abstinence + sleep restriction with two clinically-relevant approaches to situations where too little or too much glucocorticoid action is suspected: glucocorticoid replacement and receptor antagonism. The functional outcome measure will be the degree of mitigation of opioid seeking, measured both by environmentally cued and non-cued responses and by footshock-induced reinstatement. The proposed research is innovative because it will provide mechanistic evidence of a role for persistent sleep deficiency in perpetuating vulnerability to relapse. These studies will provide a basis for novel translational approaches to target mechanisms that are demonstrated to cause increased vulnerability to relapse.